Bi-allelic c.181_183delTGT in BTB domain of KLHL7 is associated with overlapping phenotypes of Crisponi/CISS1-like and Bohring-Opitz like syndrome

Kanthi, Anil; Hebbar, Malavika; Bielas, Stephanie; Girisha, Katta M.; Shukla, Anju

doi:10.1016/j.ejmg.2018.08.009

Cited by 7 publications

(15 citation statements)

References 18 publications

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“…Recently, individuals with an overlapping phenotype of CS/CISS, BOS and/or RP caused by KLHL7 variants were identified. Hence, physicians have to be aware of the range of variability in presentation of individuals with KLHL7 variants …”

Section: Differential Diagnosticmentioning

confidence: 99%

Crisponi/cold‐induced sweating syndrome: Differential diagnosis, pathogenesis and treatment concepts

et al. 2019

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Crisponi/cold-induced sweating syndrome (CS/CISS) is an autosomal recessive disease characterized by hyperthermia, camptodactyly, feeding and respiratory difficulties often leading to sudden death in the neonatal period. The affected individuals who survived the first critical years of life, develop cold-induced sweating and scoliosis in early childhood. The disease is caused by variants in the CRLF1 or in the CLCF1

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Section: Differential Diagnosticmentioning

confidence: 99%

Crisponi/cold‐induced sweating syndrome: Differential diagnosis, pathogenesis and treatment concepts

et al. 2019

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“…In contrast, modeling KHLH7 mutations that are implicated in Crisponi and BOS3, c.1115G > A:p.(Arg372Gln) and c.1258C > T:p.(Arg420Cys), revealed that they were localized to the Kelch domain (Figure 5b pink circles) [12–15]. More specifically, these arginine amino acids were located at structurally analogous positions in blades III and IV within the inter-blade loop.…”

Section: Resultsmentioning

confidence: 99%

“…Structural analysis of the variants seen in our cohort when compared to reported recessive loss-of-function alleles suggests a domain-dependent correlation between genotype and phenotype. Mutations in the 3-box motif of the BACK domain appear to cause interruptions to the assembly of Cul3 ligase, and, consequently, the UPP degradation pathway in a dominant negative fashion [ 6, 7, 10, 13, 15]. Interruptions of the UPP degradation pathway have been implicated in other genetic etiologies of RP, such as TOPORS mediated adRP and the p.Pro23His variant in RHO mediated adRP [32].…”

Section: Discussionmentioning

confidence: 99%

Novel mutations in the 3-box motif of the BACK domain of KLHL7 associated with nonsyndromic autosomal dominant retinitis pigmentosa

Carvalho

Sun

et al. 2019

Orphanet J Rare Dis

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BackgroundMutations in the Kelch-like protein 7 (KLHL7) represent a recently described and, to date, poorly characterized etiology of inherited retinal dystrophy. Dominant mutations in KLHL7 are a cause of isolated, non-syndromic retinitis pigmentosa (RP). In contrast, recessive loss-of-function mutations are known to cause Crisponi or Bohring-Opitz like cold induced sweating syndrome-3 (BOS-3). In this study, the phenotype and progression of five unrelated patients with KLHL7 mediated autosomal dominant RP (adRP) are characterized. Clinical evaluation of these patients involved a complete ophthalmic exam, full-field electroretinography (ffERG), and imaging, including fundus photography, spectral domain optical coherence tomography (SD-OCT), short wavelength fundus autofluorescence (SW-AF), and near-infrared fundus autofluorescence (NIR-AF). Molecular diagnoses were performed using whole-exome sequencing or gene panel testing. Disease progression was monitored in three patients with available data for a mean follow up time of 4.5 ± 2.9 years. Protein modeling was performed for all variants found in this study in addition to those documented in the literature for recessive loss-of-function alleles causing Crisponi or Bohring-Opitz like cold-induced sweating syndrome.ResultsGenetic testing in three patients identified two novel variants within the 3-box motif of the BACK domain: c.472 T > C:p.(Cys158Arg) and c.433A > T:p.(Asn145Tyr). Clinical imaging demonstrated hyperautofluorescent ring formation on both SW-AF and NIR-AF in three patients, with diffuse peripheral and peripapillary atrophy seen in all but one case. SD-OCT demonstrated a phenotypic spectrum, from parafoveal atrophy of the outer retina with foveal sparing to widespread retinal thinning and loss of photoreceptors. Incidence of cystoid macular edema was high with four of five patients affected. Protein modeling of dominant alleles versus recessive loss-of-function alleles showed dominant alleles localized to the BTB and BACK domains while recessive alleles were found in the Kelch domain.ConclusionsWe report the phenotype in five patients with KLHL7 mediated adRP, two novel coding variants, and imaging biomarkers using SW-AF and NIR-AF. These findings may influence future gene-based therapies for adRP and pave the way for mechanistic studies that elucidate the pathogenesis of KLHL7-mediated RP.

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“…8,[15][16][17] Regarding the variants of KLHL7, only 13 have been identified in 21 patients so far, two of whom participated in the present study. [11][12][13][18][19][20][21] In this study, we present the molecular basis of CS/CISS-like phenotypes in 23 clinically well-characterized patients, combining data gathered from two centers in Turkey. This report expands the clinical and molecular spectrum of CRLF1 and KLHL7-related disorders.…”

mentioning

confidence: 99%

“…Stepwise targeted Sanger sequencing had been applied initiating with the CRLF1 gene (NM_004750.5) and followed with the CLCF1 gene (NM_013246.3) for patients with classical CS/CISS findings and the KLHL7 gene (NM_001031710.3) was screened for patients with CS/CISS-like phenotype (Supplement Table 1). Proband of one family had been molecularly investigated by whole-exome sequencing at an external center with a large cohort of arthrogryposis and his variant was previously published (proband BAB10699 in reference 19). Clin-Var database 22 and comprehensive literature search were used for variant analysis.…”

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confidence: 99%

Clinical and molecular genetic findings of Crisponi/cold‐induced sweating syndrome (CS/CISS) spectrum in patients from Turkey

et al. 2022

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Crisponi/cold-induced sweating syndrome (CS/CISS) is a rare autosomal recessive disorder characterized by episodic hyperthermia, arthrogryposis, impaired feeding ability, and respiratory distress. The classic CS/CISS is mainly associated with CRLF1 and, rarely, CLCF1. PERCHING syndrome, previously known as CS/CISS type-3 associated with biallelic pathogenic variants in KLHL7, is notable for its few overlapping manifestations. This study presents genotype-phenotype relationships in CS/CISSlike spectrum associated with CRLF1 and KLHL7. Clinical findings of 19 patients from 14 families and four patients from three families were found in association with six different CRLF1 and three different KLHL7 variants, respectively. c.167T>C and c.713delC of the CRLF1 gene and the c.642G>C of the KLHL7 were novel. The c.708_709delCCinsT allele of CRLF1 was identified in 10 families from the Mardin province of Turkey, underlining that an ancestral haplotype has become widespread.CRLF1-associated phenotypes revealed novel manifestations such as prenatal oligohydramnios, benign external hydrocephalus, previously unreported dysmorphic features emerging with advancing age, severe palmoplantar keratoderma and facial erythema, hypopigmented macules and streaks, and recurrent cardiac arrests. KLHL7 variants presented with glabellar nevus flammeus, blepharophimosis, microcephaly, thin corpus callosum, and cleft palate. Abnormalities of sweating, observed in one patient reported herein, is known to be very rare among KLHL7-related phenotypes.

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Bi-allelic c.181_183delTGT in BTB domain of KLHL7 is associated with overlapping phenotypes of Crisponi/CISS1-like and Bohring-Opitz like syndrome

Cited by 7 publications

References 18 publications

Crisponi/cold‐induced sweating syndrome: Differential diagnosis, pathogenesis and treatment concepts

Crisponi/cold‐induced sweating syndrome: Differential diagnosis, pathogenesis and treatment concepts

Novel mutations in the 3-box motif of the BACK domain of KLHL7 associated with nonsyndromic autosomal dominant retinitis pigmentosa

Clinical and molecular genetic findings of Crisponi/cold‐induced sweating syndrome (CS/CISS) spectrum in patients from Turkey

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